This invention relates to apparatus for the non-invasive quantitative measurement of a substance in a human or animal body, and in particular to apparatus for such measurement utilising electromagnetic radiation.
Whilst apparatus according to the invention may be used in the quantitative measurement of a number of substances in the body it will primarily be described, by way of example, for use in determining a quantitative value for tissue oxygenation.
Adequate oxygenation of tissues of patients in the intensive care unit (ICU) is a fundamental requirement, yet at present there is no routine method of non-invasively monitoring intracellular oxygen in intact tissues. Few technologies exist which have the capability to do this. Non-invasive techniques capable of monitoring oxidative metabolism include Magnetic Resonance Spectroscopy (.sup.31 P MRS); Positron emission tomography (PET); NADH fluorimetry; Somatosensory evoked potentials (CNS only); optical monitoring, e.g. visible spectroscopy, Near Infra Red (NIR) multi-wavelength spectroscopy.
Primary objectives in both adult and neonatal intensive care include prevention of brain injury and maintenance of normal neurological function. Most current monitoring techniques in both of these areas determine oxygenation at sites distant from the brain and do not directly access either cerebral oxygen delivery or oxygen utilisation of the brain.
There is, therefore, a real need for a reliable, safe and continuous method of monitoring the oxygen available at the cellular level for respiration in the brain (and other organs) during critical care situations.
Hypoxia (or hypoxaemia), which is the absence of sufficient oxygen in tissues and blood, is the major cause of anaesthetic-related deaths and is also symptomatic of a number of naturally occurring and technically induced health problems and disorders. Damage resulting from a hypoxic state can occur in a matter of seconds and is often irreversible. Intracellular hypoxia causes diverse physiological responses that depend on the sensitivity of different organ systems to oxygen deprivation.
In normal tissues the continuous delivery of oxygen closely matches the oxidalive metabolic requirements of the tissue. These requirements are determined locally and met primarily by regional increases in blood flow and oxygen extraction. Thus, when functional activity is high, oxygen delivery and extraction increase to keep pace with metabolic demand. Similar responses occur in hypoxia when tissues maintain oxygen uptake by maximising blood flow and oxygen extraction.
At present, systemic measurement of oxygen delivery and uptake are used to draw inferences about the availability of oxygen for intracellular processes. These systemic parameters can be helpful when the total supply of oxygen for the body becomes limited; however, they are unsuitable when various tissues respond and adapt differently to changes in regional oxygenation and metabolism.
Thus, any instrument capable of providing continuous, real time, quantitative information on cerebral oxidative metabolism and haemoglobin oxygenation would have significant advantages over current monitoring capabilities.
Living organisms require a continual import of free energy for three major purposes; the performance of mechanical work in muscle contraction and other cellular movements, the active transport of molecules and ions, and the synthesis of macro-molecules and other biomolecules from simple precursors.
Essentially all of the energy needed for cellular metabolism is provided by glucose. Each molecule of glucose provides the energy to form many molecules of ATP (adenosine triphosphate). This occurs by means of a series of electron transfer reactions in which the hydrogen atoms from the glucose are catalytically combined with the oxygen present in cells, to form water. This process occurs in the mitochondria with the flavoprotein-cytochrome chain of enzymes responsible for the transfer of electrons to oxygen. Each enzyme in the chain is reduced and then re-oxidized as the electron is passed down the line. The enzyme complex, cytochrome c oxidase (abbreviated cyt aa.sub.3) is the terminal member of the mitochondrial respiratory chain and catalyses approximately 95% of all oxygen utilisation in the human body. In the parallel process of oxidalive phosphorylation, free energy is conserved in the form of high energy phosphate bonds and stored primarily as ATP and creatinine phosphate. The mechanism is chemiosmotic and involves the transfer of protons across an insulating membrane (the inner membrane that forms the cristae of the mitochondria) the transfer being driven by oxidation in the respiratory chain. (Oxidation is the combination of substance with oxygen, or loss of hydrogen, or loss of electrons; the corresponding reverse processes are called reduction.) Cyt aa.sub.3 is, therefore, central to cell metabolism. Cyt aa.sub.3 is present in measurable quantities in the cerebral cortex and other tissue.
When oxygen is unavailable to cyt aa.sub.3 the enzyme is reduced, the rate of electron transport slows, and oxidative phosphorylation decreases. Therefore, the redox state of cyt aa.sub.3 is an important indicator of energy provision during pathologic states characterised by disordered oxygen delivery and utilisation. Thus, an ability to continuously measure and monitor the redox state of this oxygen-utilising enzyme to vivo would provide decisive information on the parameter of oxygen sufficiency in tissue(s) or organ(s) in question.
As is well known, radiation in the near infra-red region, having wavelengths in the range 700-1300 nm, can penetrate soft tissue and bone surrounding a living organ, and the emerging light can be related to oxidative metabolism. In addition, and of significant importance, it is further known that cyt aa.sub.3 in living body tissue exhibits an oxygen-dependent absorption band in the 700 to 1300 nm wavelength range.
When this key enzyme in oxidative reactions is in the presence of sufficient oxygen, a weak absorption band exists in the 780 to 870 nm region with a maximum at a wavelength of about 820 to 840 nm. The absence of oxygen results in a complete reduction of the enzyme and the disappearance of the absorption band.
British Patent Specification 2075668 discloses apparatus for providing information regarding the oxygenation of specific tissue or organs (e.g. the brain), by monitoring the absorption by cyt aa.sub.3, of NIR radiation having wavelengths in the abovementioned region.
Haemoglobin also absorbs light in the near infra-red region of the spectrum. In addition, haemoglobin absorbs differently depending on whether it is present in its oxygenated form (HbO.sub.2) or reduced form (Hb). Thus the optical signals are affected by the amounts of arterial and venous blood in the field of observation. To obtain the cyt aa.sub.3 signal it is therefore necessary to determine, and remove, the Hb and HbO.sub.2 contributions to light absorption in the NIR, and eliminate their interference with the cyt aa.sub.3 signal. To do this multiple monochromatic light sources are required. Such light sources, together with suitable algorithms, enable simultaneous equations to be constructed and solved for the three unknowns (Hb, HbO.sub.2, cyt aa.sub.3) giving qualitative information about these compounds.
Since three overlapping absorption spectra must be de-convoluted, absorption data are needed for a minimum of three NIR wavelengths to measure contributions by the three molecular species of interest. (Four wavelength algorithms provide more accurate descriptions of NIR absorption and scattering by tissues).
Such apparatus is useful as a trend monitor but quantitative results are unattainable since calibration of the apparatus is not possible for the following reasons:
a) Material such as skin or bone through which the radiation is passing will reduce the radiation intensity both before and after passing through the particular tissue of interest; this will vary from patient to patient. PA0 b) The efficiency with which the incident radiation is guided into the body is unknown and variable, as is the efficiency with which the radiation is transferred from the body to the detector. PA0 c) The path length of the radiation within the tissue under test cannot be accurately determined and can only be estimated by photon time of flight measurements. PA0 a) emitter means capable of emitting electromagnetic radiation, said emitter means being arrangeable in use in contact with the skin, tissue or organ of a patient, PA0 b) first radiation detection means spaced from said emitter means, and arrangeable in use in contact with the skin, tissue or organ of said patient, PA0 c) means for producing a first electrical output signal dependent on the intensity of the radiation detected by said first radiation detection means, PA0 d) second radiation detection means spaced from said emitter means by a distance greater than said spacing between said first radiation detection means and said emitter means, and arrangeable in use in contact with the skin, tissue or organ of said patient, PA0 e) means for producing a second electrical output signal dependent on the intensity of the radiation detected by said second radiation detection means, and PA0 f) means for processing said first and second output signals such that a quantified index of said substance in the body is obtainable.
As is well known in the art, the path length is critical to the intensity of radiation detected by the detector. This relationship is given by the Beer-Lambert Law. EQU ln(I.sub.o /I)=d.times.E.times.c
where In=2.303 log.sub.10 I.sub.o =Intensity of source radiation impinging on the sample I=Intensity of radiation transmitted through the sample E=Absorption (extinction) coefficient of the solute species at the wavelength of the source radiation impinged on the sample d=Optical distance or path length (travel path length of radiation transmitted through sample) c=Concentration of substance being measured.
These uncertainties and variables mean that the use of apparatus of the type described above is not a quantitative technique, that is it cannot be applied from patient to patient without calibrating the instrument for each individual patient.